The plant polyphenols, in particular derivatives of cis-stilbene, are promising group of anti-carcinogenic agents. Combretastatin A-4 (CA-4, 3′-hydroxy-3,4,4′,5-tetramethoxy-cis-stilbene) is the leading substance for compounds of such structure and the best-known tubulin polymerization inhibitor (FIG. 1). One of the CA-4 pro-drug form—disodium phosphate (Zybrestat™)—is currently in phase 3 of clinical trials for the treatment of very aggressive and drug resistant form of anaplastic thyroid cancer (Siemann, D. W.; Chaplin, D. J.; Walicke, P. A. Expert Opin. Inv. Drugs 2009, 18, 189-197).

Antimitotic activity of CA-4 is the result of its interaction with tubulin—protein forming microtubules in the cell nucleus—considered as the best molecular target for anticancer chemotherapeutics. Noteworthy, cis-stilbene derivatives accelerate depolymerization of tubulin inhibiting the formation of microtubules therefore, while the trans-stilbenes influence in the process of tubulin polymerization. Compounds of both groups, known as microtubule-interfering agents (MIAs), have affinity to the different binding sites on the tubulin surface, which affects the balance between two processes inside cancer cells, polymerization and depolymerization of microtubules (Singh, P.; Rathinasamy, K.; Mohan, R.; Panda, D. IUBMB Life 2008, 60, 368-375). It leads to arresting the cell cycle in the G2/M phase, which is accompanied by the activation of apoptotic signalling pathways (Li, H.; Wu, W. K. K.; Zheng, A.; Che, C. T.; Yu, L. et al. Biochem. Pharmacol. 2009, 78, 1224-1232). In addition, combretastatin shows strong antiangiogenic activity by selectively inhibition of the new blood vessels formation in cancer tissue (Thorpe, E. P. Clin. Cancer Res. 2004, 10, 415-4270. Tozer, G. M.; Kanthou, C.; Parkins, C. S.; Hill, S. A. Int. J. Exp. Pathol. 2001, 83, 21-38).
In recent years, a number of structural modifications of CA-4 were performed allowing for identification of substituents affecting the activity of different analogues. It has been found that the presence of methoxy radicals at 3-, 4-, 5-positions in phenyl ring is crucial in the context of pharmacological effect (Tron, G. C.; Pirali, T.; Sorba, G.; Pagliai, F.; Busacca, S.; Genazzani, A. J. Med. Chem. 2006, 49, 3033-3044). On the other hand, modification involving ethylene chain stiffening with an oxazole or N-methylimidazole ring proved to be effective in preventing the conversion from cis to the trans isomer, which increased the cytotoxic effect against cancer cells. At the same time efforts aimed at improving the bioavailability of CA-4 derivatives made it possible to obtain the corresponding prodrugs—the aforementioned Zybrestat™ (Tron, G. C.; Pirali, T.; Sorba, G.; Pagliai, F.; Busacca, S.; Genazzani, A. J. Med. Chem. 2006, 49, 3033-3044) and serine derivative—Omrabulin™ or AVE8062 (Delmonte, A., Sessa, C.; Expert Opin. Inv. Drugs 2009, 18, 1541-1548). These compounds (FIG. 2) are subject to biotransformation—dephosphorylation and deacetylation respectively—to biologically active molecules.
